CPEB is a sequence-specific RNA binding protein that regulates polyadenylation-induced translation during vertebrate development. While infertile, a global CPEB knockout mouse is viable and normal size. However, mouse embryo fibroblasts (MEFs) derived from these knockout (KO) animals are immortal whereas MEFs derived from wild type (WT) animals, as expected, become senescent after 7-9 passages in culture. Infection of early passage KO MEFs with a virus expressing CPEB rescues the senescence phenotype;infection of late passage immortalized KO MEFs has no effect. Moreover, infection of early passage WT MEFs with a CPEB-expressing virus induces premature senescence while infection of immortalized WT MEFs has no effect. These results demonstrate that CPEB is necessary for cell senescence. Additional experiments indicate that i.) CPEB regulation of cell senescence requires the tumor suppressors p53 and p19ARF, ii.) CPEB-mediated translation controls senescence, and iii.) the CPEB KO MEFs may be partially transformed.
The specific aims of this proposal include the determination of the underlying molecular and cellular mechanisms by which CPEB regulates senescence in mouse cells. Additional evidence is presented indicating that CPEB also controls senescence in human cells. Many of the techniques we will employ are those we have used for several years to study CPEB-regulated translation and include an analysis of RNA-protein interactions, protein-protein interactions, examination of poly(A) tail length, and immuno-cytochemistry. These proposed experiments deal directly with cancer etiology and the ageing process, which is central to the mission of NIH. This proposal focuses on new molecules that regulate cell senescence. Because this process is strongly linked to cancer and ageing, it clearly has important implications for human health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030323-04
Application #
7795784
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Velazquez, Jose M
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$323,198
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Udagawa, Tsuyoshi; Swanger, Sharon A; Takeuchi, Koichi et al. (2012) Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex. Mol Cell 47:253-66
Alexandrov, Ilya M; Ivshina, Maria; Jung, Dae Young et al. (2012) Cytoplasmic polyadenylation element binding protein deficiency stimulates PTEN and Stat3 mRNA translation and induces hepatic insulin resistance. PLoS Genet 8:e1002457
Nagaoka, Kentaro; Udagawa, Tsuyoshi; Richter, Joel D (2012) CPEB-mediated ZO-1 mRNA localization is required for epithelial tight-junction assembly and cell polarity. Nat Commun 3:675
D'Ambrogio, Andrea; Gu, Weifeng; Udagawa, Tsuyoshi et al. (2012) Specific miRNA stabilization by Gld2-catalyzed monoadenylation. Cell Rep 2:1537-45
Oruganty-Das, Aparna; Ng, Teclise; Udagawa, Tsuyoshi et al. (2012) Translational control of mitochondrial energy production mediates neuron morphogenesis. Cell Metab 16:789-800
Darnell, Jennifer C; Van Driesche, Sarah J; Zhang, Chaolin et al. (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247-61
Groppo, Rachel; Richter, Joel D (2011) CPEB control of NF-kappaB nuclear localization and interleukin-6 production mediates cellular senescence. Mol Cell Biol 31:2707-14
Burns, David M; D'Ambrogio, Andrea; Nottrott, Stephanie et al. (2011) CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation. Nature 473:105-8
Burns, David M; Richter, Joel D (2008) CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation. Genes Dev 22:3449-60